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Science. 2019 Aug 9;365(6453):599-604. doi: 10.1126/science.aax3649.

A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
2
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
3
Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
5
The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
6
Department of Biomedical Informatics, Harvard University, Boston, MA 02115, USA.
7
Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
8
Department of Internal Medicine III, University of Ulm, 89081 Ulm, Germany.
9
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
10
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
11
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
12
Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
13
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. benjamin_ebert@dfci.harvard.edu.
14
Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Abstract

TP53, which encodes the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic human leukemia cell lines of the most common TP53 missense mutations. Functional, DNA-binding, and transcriptional analyses revealed loss of function but no GOF effects. Comprehensive mutational scanning of p53 single-amino acid variants demonstrated that missense variants in the DNA-binding domain exert a dominant-negative effect (DNE). In mice, the DNE of p53 missense variants confers a selective advantage to hematopoietic cells on DNA damage. Analysis of clinical outcomes in patients with acute myeloid leukemia showed no evidence of GOF for TP53 missense mutations. Thus, a DNE is the primary unit of selection for TP53 missense mutations in myeloid malignancies.

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PMID:
31395785
DOI:
10.1126/science.aax3649

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